On his release in 1924, MacBride studied law at University College Dublin and resumed his IRA activities.[4] He worked briefly for Éamon de Valera as his personal secretary, travelling with him to Rome to meet various dignitaries.

In January 1925, on his twenty-first birthday, MacBride married Catalina "Kid" Bulfin, a woman four years his senior who shared his political views.[5] Bulfin was the daughter of the Irish nationalist publisher and travel-writer William Bulfin.

Before returning to Dublin in 1927, where he became the IRA's Director of Intelligence, MacBride worked as a journalist in Paris and London. Soon after his return, he was arrested and charged with the murder of politician Kevin O'Higgins, who had been assassinated near his home in Booterstown, County Dublin. MacBride was able to prove, however, that he was on his way back to Ireland at the time, as he was able to call unionist-turned-Cumann na nGaedheal politician Bryan Cooper, whom he had met on the boat home, as a witness. He was then charged with being a subversive and interned in Mountjoy Prison.[6]

Towards the end of the 1920s, after many supporters had left to join Fianna Fáil, some members of the IRA started pushing for a more left-wing agenda. After the IRA Army Council voted down the idea, MacBride launched a new movement, Saor Éire ("Free Ireland"), in 1931. Although it was a non-military organisation, Saor Éire was declared unlawful along with the IRA, Cumann na mBan and nine other bodies. MacBride, meanwhile, became the security services' number-one target.[7]

In 1936, the IRA's chief of staffMoss Twomey was sent to prison for three years. He was replaced by MacBride. At the time, the movement was in a state of disarray, with conflicts between several factions and personalities. Tom Barry was appointed chief of staff to head up a military operation against the British, an action with which MacBride did not agree.[8]

In 1937, MacBride was called to the bar. He then resigned from the IRA when the Constitution of Ireland was enacted later that year. As a barrister, MacBride frequently defended IRA political prisoners, but was unsuccessful in stopping the execution in 1944 of Charlie Kerins, convicted of killing Garda Detective Denis O'Brien in 1942. In 1946, during the inquest into the death of Seán McCaughey, MacBride embarrassed the authorities by forcing them to admit that the conditions in Portlaoise Prison were inhumane.[9]

In 1951, MacBride controversially ordered Noël Browne to resign as a minister over the Mother and Child Scheme after it was attacked by the Irish Catholic hierarchy and the Irish medical establishment.[13] Whatever the merits of the scheme, or of Dr. Browne, MacBride concluded in a Cabinet memorandum:

"Even if, as Catholics, we were prepared to take the responsibility of disregarding [the Hierarchy's] views, which I do not think we can do, it would be politically impossible to do so . . . We are dealing with the considered views of the leaders of the Catholic Church to which the vast majority of our people belong; these views cannot be ignored."[14]

Also in 1951, Clann na Poblachta was reduced to two seats after the general election. MacBride kept his seat and was re-elected again in 1954. Opposing the internment of IRA suspects during the Border Campaign (1956–62), he contested both the 1957 and 1961 general elections but failed to be elected both times. He then retired from politics and continued practising as a barrister. He expressed an interest in running as an independent candidate for the 1983 Irish presidential election, but he did not receive sufficient backing and ultimately did not contest.

He drafted the constitution of the Organisation of African Unity (OAU); and also the first constitution of Ghana (the first UK African colony to achieve independence) which lasted for nine years until the coup of 1966.

In 1973, he was elected by the General Assembly to the post of High Commissioner for Namibia, with the rank of Assistant Secretary-General. The actions of his father John MacBride in leading the Irish Transvaal Brigade (known as MacBride's Brigade) for the Boers against the British Army, in the Boer War, gave Seán MacBride a unique access to South Africa's apartheid government. In 1977, he was appointed president of the International Commission for the Study of Communication Problems, set up by UNESCO. In 1980 he was appointed Chairman of UNESCO.

MacBride's work was awarded the Nobel Peace Prize (1974)[16] as a man who "mobilised the conscience of the world in the fight against injustice". He later received the Lenin Peace Prize (1975–76) and the UNESCO Silver Medal for Service (1980).

In 1982, MacBride was chairman of the International Commission to enquire into reported violations of International Law by Israel during its invasion of the Lebanon. The other members were Richard Falk, Kader Asmal, Brian Bercusson, Géraud de la Pradelle, and Stefan Wild. The commission's report, which concluded that "the government of Israel has committed acts of aggression contrary to international law", was published in 1983 under the title Israel in Lebanon.[18]

In his later years, MacBride lived in his mother's home, Roebuck House, that served as a meeting place for many years for Irish nationalists, as well as in the Parisian arrondissement where he grew up with his mother, and enjoyed strolling along boyhood paths. He maintained a soft-spoken, unassuming demeanor despite his fame. While strolling through the Centre Pompidou Museum in 1979, and happening upon an exhibit for Amnesty International, he whispered to a colleague "Amnesty, you know, was one of my children."[citation needed]

Seán MacBride died in Dublin on 15 January 1988, eleven days before his 84th birthday. He is buried in Glasnevin Cemetery, among Irish patriots, in a simple grave with his mother and wife who died in 1976.